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Published on: December 21, 2011
Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and
Yu Sun1, Guochang Hu, Xiumei Zhang
1Department of Pharmacology (m/c 868), University of Illinois at Chicago, Chicago, IL 60612, USA.
Rationale:
Oxidants are important signaling molecules known to increase endothelial permeability, although the mechanisms underlying permeability regulation are not clear.
Objective:
To define the role of caveolin-1 in the mechanism of oxidant-induced pulmonary vascular hyperpermeability and edema formation.
Methods And Results:
Using genetic approaches, we show that phosphorylation of caveolin-1 Tyr14 is required for increased pulmonary microvessel permeability induced by hydrogen peroxide (H(2)O(2)). Caveolin-1-deficient mice (cav-1(-/-)) were resistant to H(2)O(2)-induced pulmonary vascular albumin hyperpermeability and edema formation. Furthermore, the vascular hyperpermeability response to H(2)O(2) was completely rescued by expression of caveolin-1 in cav-1(-/-) mouse lung microvessels but was not restored by the phosphorylation-defective caveolin-1 mutant. The increase in caveolin-1 phosphorylation induced by H(2)O(2) was dose-dependently coupled to both increased (125)I-albumin transcytosis and decreased transendothelial electric resistance in pulmonary endothelial cells. Phosphorylation of caveolin-1 following H(2)O(2) exposure resulted in the dissociation of vascular endothelial cadherin/beta-catenin complexes and resultant endothelial barrier disruption.
Conclusions:
Caveolin-1 phosphorylation-dependent signaling plays a crucial role in oxidative stress-induced pulmonary vascular hyperpermeability via transcellular and paracellular pathways. Thus, caveolin-1 phosphorylation may be an important therapeutic target for limiting oxidant-mediated vascular hyperpermeability, protein-rich edema formation, and acute lung injury.
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